CN112608311B - Chiral [3.3.1] azacycloindole alkaloid derivative and preparation method and application thereof - Google Patents
Chiral [3.3.1] azacycloindole alkaloid derivative and preparation method and application thereof Download PDFInfo
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- CN112608311B CN112608311B CN202011541694.1A CN202011541694A CN112608311B CN 112608311 B CN112608311 B CN 112608311B CN 202011541694 A CN202011541694 A CN 202011541694A CN 112608311 B CN112608311 B CN 112608311B
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- benzyl
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- 150000003797 alkaloid derivatives Chemical class 0.000 title claims abstract description 18
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- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
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- 238000000034 method Methods 0.000 claims abstract description 11
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- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Chemical class C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 claims abstract description 4
- 229940126062 Compound A Drugs 0.000 claims abstract description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
The invention provides a chiral [3.3.1] azacycloindole alkaloid derivative and a preparation method and application thereof, wherein the preparation method comprises the following steps: under the action of a chiral quaternary phosphonium salt catalyst, dissolving a compound A and a compound B in an organic solvent, adding alkali, and reacting to obtain the chiral [3.3.1] aza-bridged indole alkaloid derivative. The preparation method has the advantages of simple process, mild reaction conditions and high yield, and the obtained product has excellent enantioselectivity and diastereoselectivity, is a core framework of a plurality of natural product molecules, chiral drugs and intermediates thereof, and has very strong practical application value. The compound provided by the invention can effectively inhibit various tumor cells, such as human colon cancer cells, lung cancer cells, melanoma cells, breast cancer cells, in-situ pancreatic cancer cells and pancreatic cancer cells, and has a wide prospect in preparation of medicines for preventing and/or treating tumors.
Description
Technical Field
The invention belongs to the technical field of chemical industry and medicine, and particularly relates to a chiral [3.3.1] azacycloindole alkaloid derivative and a preparation method and application thereof.
Background
Indole alkaloids occur widely in nature and are the core building blocks of many natural products and important pharmaceutically active molecules. The [3.3.1] azabridged ring skeleton molecule is the core skeleton of indole alkaloids such as Macroine, Sarpagine and the like, and the natural alkaloids can show a plurality of important physiological and pharmaceutical activities and are widely used for disease treatment, such as treatment of nervous system diseases, Alzheimer disease, tumor resistance, sedation, virus resistance and the like. Due to the unique structure, relative rigidity and the containing of the double-ring nitrogen bridged ring framework, the synthesis, especially the asymmetric synthesis, is always a research difficulty and a challenge in organic chemistry. Although sporadic reports exist, most of the reported examples are constructed by means of total synthesis or semi-synthesis, and multiple reactions and chiral substrate synthesis are required. These process disadvantages are quite evident: 1) the reaction process is long and the operation is complex; 2) the total yield is very low, and the efficiency is low; 3) the stereoselectivity of the product is low; 4) the product has a single structure and is very limited. It is worth mentioning that there has been no report on the catalytic asymmetric synthesis methodology of such framework molecules. Therefore, the development of a high-efficiency catalytic asymmetric synthesis method for quickly constructing chiral aza [3.3.1] bridged ring skeleton molecules and developing the pharmacological activity of the molecules has very important research significance and value.
Disclosure of Invention
The invention aims to provide chiral [3.3.1] azacycloindole alkaloid derivatives, and a preparation method and application thereof.
A chiral [3.3.1] azacycloindole alkaloid derivative, comprising the structural formula I and its corresponding enantiomers and diastereomers, or a salt, or a crystalline form thereof:
wherein,
R1is C1-20Alkyl, alkoxy, benzyl, phenyl or substituted phenyl, naphthyl, ketocarbonyl or substituted ketocarbonyl, ester, nitro, trifluoromethyl, sulfonyl, heteroaromatic;
R2is hydrogen, C1-20Alkyl, benzyl, t-butyloxycarbonyl, acyl, p-methoxybenzyl (PMB), t-butyloxycarbonyl (Boc), chloroformate group;
R3is hydrogen, C1-20Alkyl, alkoxy, aryl or substituted aryl, benzyl or substituted benzyl;
R4is hydrogen, C1-20Alkyl, nitro, ketocarbonyl, aldehyde, ester, sulfonyl, trifluoromethyl;
R5is hydrogen, C1-20Alkyl, aryl or substituted aryl, alkoxy, benzyl, halogen, heteroatoms;
R6is hydrogen, tert-butyloxycarbonyl, acyl, benzyl, chloroformate group;
ar is aryl or substituted aryl, indole ring or substituted indole ring group, heterocycle or substituted heterocycle.
Further, R1Is C1-20Alkyl (e.g. ethyl, propyl, isopropyl, C3 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, goldAdamantyl), phenyl or substituted phenyl (e.g., halogen, methyl, methoxy-substituted phenyl), naphthyl, sulfonyl, aromatic heterocycle (e.g., five-membered heterocycle or substituted five-membered heterocycle, six-membered heterocycle or substituted six-membered heterocycle, etc.);
R2is hydrogen, C1-20Alkyl (e.g., methyl, ethyl), benzyl, p-methoxybenzyl (PMB), tert-butoxycarbonyl (Boc), chloroformate (Cbz);
R3is hydrogen, C1-20Alkyl (e.g., methyl);
R4is nitro or ester group;
R5is hydrogen, C1-20Alkyl (e.g., methyl), alkoxy (e.g., methoxy), halogen;
R6hydrogen, acyl (e.g., acetyl);
ar is aryl or substituted aryl, indole ring or substituted indole ring group, furan, pyrrole, pyridine, thiophene, quinoline, isoquinoline, benzofuran, benzothiophene, benzopyridine.
Further, the structural formula is as follows but not limited to the following structure:
the preparation method of the chiral [3.3.1] azacycloindole alkaloid derivative comprises the following steps:
under the action of a chiral quaternary phosphonium salt catalyst, dissolving a compound A and a compound B in an organic solvent, adding alkali, and reacting to obtain a chiral [3.3.1] aza-bridged indole alkaloid derivative, namely a compound shown in a formula I;
the synthetic route is as follows:
further, the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, ethanol, acetonitrile, toluene or xylene.
Further, the base is triethylamine, diisopropylethylamine, DABCO, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate heptahydrate, sodium phosphate decahydrate, sodium hydroxide, potassium hydroxide or lithium hydroxide.
Further, the reaction temperature is-78-40 ℃, and the reaction time is 6-72 h.
Further, the chiral quaternary phosphonium salt catalyst is:
wherein in the compound IV, R1Is hydrogen, C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r5Is Boc, Ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r6Is C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF4OTf, OAc or OBoc;
in the compound V, R4Is hydrogen, C1-20Alkyl, Boc, Ts, benzyl or substituted benzyl, silicon-based (preferably TBDPS, TBS, TES, TMS, TIPS, TPS); r5Is Boc, Ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r6Is C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF4OTf, OAc or OBoc.
Further, the chiral quaternary phosphonium salt catalyst is:
further, the preparation method of the chiral quaternary phosphonium salt catalyst IV comprises the following steps:
chiral trivalent phosphine is subjected to wittig reaction to prepare the quaternary phosphonium salt catalyst in one step, and the synthetic route is as follows:
dissolving trivalent phosphine in DCM, adding methyl iodide, stirring for 3 hours at room temperature, and directly concentrating to obtain a product; or adding benzyl bromide, refluxing the methylbenzene for 2 hours, cooling, spin-drying and recrystallizing to obtain a product;
wherein R is1Is hydrogen, C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, heterocyclic or substituted heterocyclic, R5Is Boc, Ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl, preferably acyl or substituted acyl; r6Is C1-20Alkyl, benzyl or substituted benzyl, phenyl or substituted phenyl, naphthyl or substituted naphthyl, heterocycle; x is halogen, BF4，BF6Or an OAc.
The preparation method of the chiral quaternary phosphonium salt catalyst V comprises the following steps:
chiral trivalent phosphine is subjected to wittig reaction to prepare the quaternary phosphonium salt catalyst in one step, and the synthetic route is as follows:
dissolving trivalent phosphine in DCM, adding methyl iodide, stirring for 3 hours at room temperature, and directly concentrating to obtain a product; or adding benzyl bromide, refluxing the methylbenzene for 2 hours, cooling, spin-drying and recrystallizing to obtain a product;
wherein R is4Is hydrogen, C1-20Alkyl, Boc, Ts, benzyl or substituted benzyl, silicon group, preferably hydrogen, silicon group (preferably TBDPS, TBS, TES, TMS, TIPS, TPS); r5Is Boc, Ts, acyl or substituted acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl, preferably, acyl or substituted acyl; r6Is C1-20Alkyl, benzyl or substituted benzyl, phenyl or substituted phenyl, naphthyl or substituted naphthyl; x is halogen (F, Cl, Br, I), BF4，BF6Or an OAc.
The preparation process of the trivalent phosphine is carried out by adopting the prior art.
The chiral [3.3.1] azacycloindole alkaloid derivative is applied to the preparation of medicaments for preventing and/or treating tumors.
Further, the tumor is human colon cancer, lung cancer, melanoma, breast cancer, in situ pancreatic cancer or pancreatic cancer.
The invention has the following beneficial effects:
(1) the chiral [3.3.1] azacycloindole alkaloid derivative is constructed in one step through simple asymmetric catalytic reaction, the synthetic method is simple, the operation is convenient, anhydrous and anaerobic conditions are not needed, the reaction does not involve transition metals, the problem of metal residue is avoided, and the method is green and environment-friendly.
(2) The catalyst used in the synthesis process is a chiral quaternary phosphonium salt catalyst which is very stable to air and water, has good water solubility and is environment-friendly.
(3) The chiral [3.3.1] azacycloindole alkaloid derivative provided by the invention has high reaction yield (yield is as high as 85-99%), high enantioselectivity (ee) and high diastereoselectivity (dr), can effectively inhibit various tumor cells, such as human colon cancer cells, lung cancer cells, melanoma cells, breast cancer cells, in-situ pancreatic cancer cells and pancreatic cancer cells, and has a wide prospect in preparation of medicaments for preventing and/or treating tumors.
Drawings
FIG. 1 is a single crystal structural diagram of Compound I-1 in example 1.
FIG. 2 is a racemic HPLC chromatogram of Compound I-6 of example 2.
FIG. 3 is an HPLC chromatogram of chiral product of compound I-6 of example 2.
FIG. 4 is a racemic HPLC chromatogram of Compound I-16 from example 3.
FIG. 5 is an HPLC chromatogram of chiral product of compound I-16 of example 3.
FIG. 6 is a racemic HPLC chromatogram of Compound I-23 of example 5.
FIG. 7 is an HPLC chromatogram of chiral product of compound I-23 of example 5.
FIG. 8 is a racemic HPLC chromatogram of Compound I-33 from example 6.
FIG. 9 is an HPLC chromatogram of chiral product of compound I-33 of example 6.
FIG. 10 is a racemic HPLC chromatogram of Compound I-40 from example 8.
FIG. 11 is an HPLC chromatogram of chiral product of compound I-40 of example 8.
FIG. 12 is a drawing of Compound I-1 of example 11H NMR spectrum.
FIG. 13 is a drawing of Compound I-1 of example 113C NMR spectrum.
FIG. 14 is a drawing of Compound I-16 of example 31H NMR spectrum.
FIG. 15 is a drawing of Compound I-16 of example 313C NMR spectrum.
FIG. 16 is a drawing of Compound I-23 of example 51H NMR spectrum.
FIG. 17 is a drawing of compound I-23 of example 513C NMR spectrum.
FIG. 18 is a drawing of Compound I-37 of example 71H NMR spectrum.
FIG. 19 is a drawing of Compound I-37 of example 713C NMR spectrum.
FIG. 20 is a drawing of Compound I-40 from example 81H NMR spectrum.
FIG. 21 is a drawing of Compound I-40 from example 813C NMR spectrum.
FIG. 22 is a drawing of Compound I-46 of example 91H NMR spectrum.
FIG. 23 is a drawing of compound I-46 of example 913C NMR spectrum.
Detailed Description
Example 1
Preparation of methyl- (6R, 7S, 13S) -8, 13-dimethyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-1):
26.1mg of compound 1a (0.1mmol) and 24.0mg of compound 2a (0.12mmol, triethylamine 15.2mg (0.15mmol), catalyst 4a (0.01mmol) and 1mL of acetonitrile are added to a reaction flask, and after stirring and mixing uniformly, the reaction is carried out at 20 ℃, the loading of the reaction catalyst is 10 mol%, the reaction is carried out for 6h, TLC shows complete consumption of the raw material 1a, extraction is carried out by ethyl acetate, and concentration is carried out by direct concentration column chromatography (petroleum ether/ethyl acetate, v/v is 40/1), so as to obtain 44.5mg of product I-1, and the single crystal structure of the product is shown in figure 1.
Characterization data: 96% yield, white solid, melting point: 173.6-174.4 ℃;1H NMR(400MHz,CDCl3)δ7.99(d,J＝7.2Hz,1H),7.68(d,J＝7.3Hz,1H),7.62(d,J＝7.9Hz,1H),7.55(dd,J＝10.5,4.4Hz,1H),7.45(t,J＝7.6Hz,1H),7.22–7.15(m,1H),7.14–7.09(m,1H),7.04(td,J＝7.2,1.0Hz,1H),6.93(d,J＝7.5Hz,1H),4.21(dd,J＝6.1,3.0Hz,1H),3.95(dd,J＝18.0,6.2Hz,1H),3.67(s,3H),3.48(s,3H),3.27(d,J＝17.9Hz,1H),3.00(dd,J＝18.0,3.0Hz,1H),2.71(d,J＝17.8Hz,1H),2.15(s,3H),1.63(s,1H).13C NMR(101MHz,CDCl3)δ198.54,174.97,145.76,137.70,136.70,136.13,133.65,133.40,128.92,128.71,128.30,126.12,125.68,124.03,121.66,121.06,119.18,112.40,109.17,61.63,53.65,52.31,40.98,39.72,37.29,29.34,24.98.；
HRMS(ESI)m/z calcd for C30H28N2O3[M+H]+＝465.2173,found＝465.2174；
The ee value was 92％,tR(major)＝10.9min,tR(minor)＝18.6min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data and the single crystal structure show that the obtained product has a correct structure.
Example 2
Preparation of methyl- (6R, 7S, 13S) -7- (2- (4-methoxyphenyl) -2-oxoethyl) -8, 13-dimethyl-5, 7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylic acid salt (I-6):
the preparation method of this example is similar to example 1, except that the raw materials and reaction conditions were changed during the reaction, the organic solvent used in the preparation process was ethyl acetate, the base was diisopropylethylamine, the catalyst was 4b, the reaction temperature was 20 ℃, and the reaction time was 6 h.
Characterization data: 92% yield, white solid, melting point: 150.4-151.2 ℃;
1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.8Hz,1H),7.68(d,J＝7.6Hz,1H),7.62(d,J＝7.9Hz,1H),7.23–7.15(m,1H),7.11(dd,J＝11.3,3.8Hz,1H),7.03(dd,J＝12.9,6.9Hz,1H),6.92(dd,J＝7.0,5.0Hz,1H),4.19(dd,J＝6.1,3.0Hz,1H),3.89(dd,J＝17.7,6.3Hz,1H),3.85(s,3H),3.67(s,3H),3.47(s,3H),3.26(d,J＝17.8Hz,1H),2.93(dd,J＝17.7,3.0Hz,1H),2.71(d,J＝17.8Hz,1H),2.15(s,3H).13C NMR(101MHz,CDCl3)δ197.07,175.02,163.76,145.79,137.69,136.26,133.69,130.66,129.81,128.92,126.12，125.88,124.03,121.65,121.01,119.16,113.84,112.36,109.17,61.57,55.51,53.64,52.28,40.50,39.96,37.33,29.34,25.02.
HRMS(ESI)m/z calcd for:C31H30N2O3[M+H]+＝479.2329,found＝479.2329.
The ee value was 94％,tR(major)＝16.8min,tR(minor)＝21.9min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 3
Preparation of methyl- (6R, 7S, 13S) -8, 13-dimethyl-7- (2-oxo-2- (1H-pyrrol-2-yl) ethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-16):
the preparation method of the example is similar to that of the example 1, only the raw materials and the reaction conditions are changed in the reaction process, the organic solvent used in the preparation process is dichloromethane, the base is potassium carbonate, the catalyst is 4c, the reaction temperature is 20 ℃, and the reaction time is 8 h.
Characterization data: 90% yield, white solid, melting point: 150.4-151.2 ℃;
1H NMR(400MHz,CDCl3)δ9.53(s,1H),7.65(dd,J＝23.8,7.7Hz,2H),7.20(dd,J＝15.4,7.8Hz,2H),7.13(t,J＝7.4Hz,1H),7.09–6.99(m,3H),6.92(d,J＝6.6Hz,2H),6.26(d,J＝3.6Hz,1H),4.08(dd,J＝6.3,3.1Hz,1H),3.71(s,3H),3.69–3.63(m,1H),3.45(s,3H),3.22(d,J＝17.8Hz,1H),2.86(dd,J＝16.8,3.1Hz,1H),2.69(d,J＝17.8Hz,1H),2.15(s,3H).；13C NMR(101MHz,CDCl3)δ188.83,175.03,145.95,137.83,136.16,133.74,132.07,129.01,126.21,125.19,124.14,121.79,121.13,119.31,119.27,117.34,112.56,111.21,109.27,61.53,53.73,52.17,40.63,40.34,37.62,29.39,25.12.
HRMS(ESI)m/z calcd for:C28H27N3O3[M+H]+＝454.2125,found＝454.2128.
The ee value was 98％,tR(major)＝15.8min,tR(minor)＝31.2min(Chiralcel IE,λ＝254nm,5％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 4
Preparation of methyl- (6R, 7S, 13S) -8, 13-dimethyl-7- (2-oxo-2- (pyridin-2-yl) ethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-19):
the preparation method of the example is similar to that of the example 1, only the raw materials and the reaction conditions are changed in the reaction process, the organic solvent used in the preparation process is chloroform, the alkali is sodium carbonate, the catalyst is 4d, the reaction temperature is 20 ℃, and the reaction time is 6 h.
Characterization data: 93% yield, white solid, melting point: 150.4-151.2 ℃;
1H NMR(400MHz,CDCl3)δ8.69–8.64(m,1H),8.11(d,J＝7.8Hz,1H),7.86(td,J＝7.7,1.7Hz,1H),7.65(dd,J＝20.7,7.6Hz,2H),7.46(ddd,J＝7.5,4.7,1.1Hz,1H),7.24(d,J＝8.2Hz,1H),7.15(ddd,J＝15.2,11.6,4.2Hz,2H),7.03(dd,J＝10.6,4.3Hz,2H),6.92(d,J＝7.5Hz,1H),4.24–4.11(m,2H),3.80(s,3H),3.51(s,3H),3.33–3.17(m,2H),2.70(d,J＝17.8Hz,1H),2.13(s,3H).13C NMR(101MHz,CDCl3)δ200.19,174.95,153.24,149.00,145.85,137.73,136.89,136.16,133.70,128.84,127.14,126.03(d,J＝8.4Hz),124.10,121.88,121.57,120.94,119.14(d,J＝13.1Hz),112.50,109.09,61.38,53.63,52.08,40.36(d,J＝11.6Hz),37.68,29.35,24.83.
HRMS(ESI)m/z calcd for:C29H27N3O3[M+H]+＝466.2125,found＝466.2123；
The ee value was 96％,tR(major)＝15.6min,tR(minor)＝18.1min(Chiralcel IB,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 5
Preparation of methyl- (6R, 7S, 13S) -7- (2-cyclopropyl-2-oxoethyl) -8, 13-dimethyl-5, 7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-23):
the preparation method of this example is similar to example 1, only the raw materials and reaction conditions are changed during the reaction, the organic solvent used in the preparation process is n-hexane, the base is diisopropylethylamine, the catalyst is 4e, the reaction temperature is 20 ℃, and the reaction time is 10 h.
Characterization data: 91% yield, white solid, melting point: 216.2-216.9 ℃;
1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.6Hz,1H),7.61(d,J＝7.9Hz,1H),7.23(d,J＝8.2Hz,1H),7.19(t,J＝7.5Hz,1H),7.15–7.10(m,1H),7.07–7.01(m,2H),6.93(d,J＝7.5Hz,1H),4.00(dd,J＝5.8,3.5Hz,1H),3.78(s,3H),3.62(s,3H),3.34(dd,J＝18.2,5.8Hz,1H),3.27(d,J＝17.9Hz,1H),2.79(dd,J＝18.2,3.5Hz,1H),2.67(d,J＝17.8Hz,1H),2.13(s,3H),1.88(tt,J＝7.9,4.6Hz,1H),1.10–1.05(m,2H),0.96–0.84(m,2H).；13C NMR(101MHz,CDCl3)δ208.77,175.02,145.73,137.67,136.14,133.65,128.89,126.12,126.06,124.04,121.58,121.01,119.16,112.14,109.15,61.59,53.61,52.45,45.81,38.87,37.26,29.31,24.93,21.10,11.09,10.78.
HRMS(ESI)m/z calcd for:C27H28N2O3[M+H]+＝429.2173,found＝429.2175；
The ee value was 99％,tR(major)＝9.1min,tR(minor)＝15.9min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 6
Preparation of methyl- (6R, 7S, 13S) -8- (4-methoxybenzyl) -13-methyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylic acid salt (I-33):
the preparation method of the example is similar to that of the example 1, only the raw materials and the reaction conditions are changed in the reaction process, the organic solvent used in the preparation process is petroleum ether, the base is triethylamine, the catalyst is 4f, the reaction temperature is 20 ℃, and the reaction time is 6 h.
Characterization data: 94% yield, white solid, melting point: 146.6-148.8 ℃;
1H NMR(400MHz,CDCl3)δ7.86–7.80(m,1H),7.71(d,J＝7.2Hz,1H),7.67(dd,J＝6.3,2.4Hz,1H),7.51(dd,J＝10.5,4.2Hz,1H),7.39(t,J＝7.7Hz,1H),7.22(t,J＝7.5Hz,1H),7.17(dd,J＝6.6,2.3Hz,1H),7.11–7.03(m,1H),6.94(d,J＝7.4Hz,1H),6.80(d,J＝8.7Hz,1H),6.69–6.57(m,1H),5.33(q,J＝16.8Hz,1H),4.17(dd,J＝6.0,2.8Hz,1H),3.81(dd,J＝18.5,6.0Hz,1H),3.62(s,3H),3.45(s,3H),3.23(d,J＝17.8Hz,1H),2.86(dd,J＝18.5,2.8Hz,1H),2.63(d,J＝17.8Hz,1H),2.18(s,3H),1.59(s,1H).13C NMR(101MHz,CDCl3)δ198.13,174.90,158.59,145.79,137.57,136.63,136.29,133.80,133.10,129.66,128.92,128.47 128.11,127.19,126.24,126.04,124.24,121.70,121.31,119.33,114.00,112.95,109.91,61.69,55.10,53.71,52.26,45.50,41.22,39.28,37.10,24.99.
HRMS(ESI)m/z calcd for:C37H34N2O4[M+H]+＝571.2591,found＝571.2590；
The ee value was 92％,tR(major)＝90.0min,tR(minor)＝106.0min(Chiralcel IE,λ＝254nm,5％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 7
Preparation of methyl- (6R, 7S, 13S) -12-methoxy-8, 13-dimethyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-37):
the preparation method of the example is similar to that of the example 1, only the raw materials and the reaction conditions are changed in the reaction process, the organic solvent used in the preparation process is petroleum ether, the base is triethylamine, the catalyst is 4g, the reaction temperature is 20 ℃, and the reaction time is 6 h.
Characterization data: 93% yield, white solid, melting point: 85.5-85.9 ℃;
1H NMR(400MHz,CDCl3)δ8.05–7.95(m,1H),7.71(d,J＝7.6Hz,1H),7.55(d,J＝7.3Hz,1H),7.46(t,J＝7.6Hz,1H),7.17(t,J＝7.5Hz,1H),7.04(t,J＝7.9Hz,1H),6.92(d,J＝7.4Hz,1H),6.83(d,J＝8.1Hz,1H),6.46(d,J＝7.8Hz,1H),4.18(dd,J＝6.3,2.6Hz,1H),4.02(dd,J＝18.1,6.4Hz,1H),3.92(s,1H),3.66(s,2H),3.46(s,2H),3.24(d,J＝17.5Hz,1H),2.99(dd,J＝18.0,2.6Hz,1H),2.70(d,J＝17.5Hz,1H),2.25(s,2H).13C NMR(101MHz,CDCl3)δ198.85,175.16,153.35,146.82,139.57,136.89,135.40,133.99,133.47,128.81,128.51(d,J＝14.5Hz),125.94,125.42,123.91,122.09,115.01,112.95,102.47,100.19,61.70,54.83,54.48,52.33,40.90,39.97,37.44,29.69,26.91.
HRMS(ESI)m/z calcd for:C31H30N2O4[M+H]+＝495.2278,found＝495.2277；
The ee value was 92％,tR(major)＝8.6min,tR(minor)＝10.6min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 8
Preparation of methyl- (6R, 7S, 13S) -8,9, 13-trimethyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-40):
the preparation method of the embodiment is similar to that of the embodiment 1, only the raw materials and the reaction conditions are changed in the reaction process, the organic solvent used in the preparation process is toluene, the base is triethylamine, the catalyst is 4h, the reaction temperature is 20 ℃, and the reaction time is 8 h.
Characterization data: 94% yield, white solid, melting point: 174.1 to 175.2 ℃;
1H NMR(400MHz,CDCl3)δ8.05–7.95(m,1H),7.69(d,J＝7.4Hz,1H),7.62–7.54(m,1H),7.51–7.43(m,1H),7.20(t,J＝7.5Hz,1H),7.06(td,J＝7.4,1.0Hz,1H),6.97–6.87(m,1H),6.82(d,J＝7.1Hz,1H),4.19(dd,J＝6.3,2.7Hz,1H),4.00(dd,J＝18.1,6.4Hz,1H),3.96(s,3H),3.49(s,3H),3.28(d,J＝17.8Hz,1H),2.98(dd,J＝18.0,2.8Hz,1H),2.75(s,1H),2.70(s,3H),2.31(s,1H),2.14(s,3H).13C NMR(101MHz,CDCl3)δ198.55,174.98,145.67,136.80,136.43,133.69,133.38,128.92,128.69,128.29,126.38,126.00,124.86,124.18,121.72,121.25,119.30,117.28,112.38,61.59,53.57,52.28,40.85,39.78,37.31,32.50,24.89,20.34.
HRMS(ESI)m/z calcd for:C31H30N2O3[M+H]+＝479.2329,found＝479.2328；
The ee value was 93％,tR(major)＝10.0min,tR(minor)＝114.2min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 9
Preparation of methyl- (6R, 7S, 13S) -2- ((tert-butoxycarbonyl) oxy) -8, 13-dimethyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylate (I-46):
the preparation method of this example is similar to example 1, only the raw materials and reaction conditions are changed during the reaction, the organic solvent used in the preparation process is xylene, the base is triethylamine, the catalyst is 4a, the reaction temperature is 20 ℃, and the reaction time is 6 h.
Characterization data: 85% yield, white solid, melting point: 190.2-191.1 ℃;
1H NMR(400MHz,CDCl3)δ8.02(d,J＝7.3Hz,1H),7.60(dd,J＝18.1,7.7Hz,1H),7.49(dd,J＝13.9,4.7Hz,2H),7.24(d,J＝8.1Hz,1H),7.16(t,J＝7.3Hz,1H),7.07(t,J＝7.3Hz,1H),6.99–6.88(m,1H),4.24(dd,J＝6.0,3.0Hz,1H),3.97(dd,J＝18.0,6.1Hz,1H),3.71(s,3H),3.52(s,3H),3.28(d,J＝17.8Hz,1H),3.03(dd,J＝18.0,3.0Hz,1H),2.69(d,J＝17.7Hz,1H),2.16(s,3H),1.61(s,9H).；13C NMR(101MHz,CDCl3)δ198.62,174.87,152.01,149.32,147.09,137.80,136.79,136.38,133.52,131.16,129.66,128.82,128.40,124.01,121.28,119.37,118.99,114.95,111.94,109.29,83.59,61.73,53.77,52.45,41.08,39.85,36.82,29.46,27.88,25.01.
HRMS(ESI)m/z calcd for:C35H36N2O6[M+H]+＝581.2646,found＝581.2649；
The ee value was 86％,tR(major)＝21.9min,tR(minor)＝13.9min(Chiralcel IA,λ＝254nm,10％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
Example 10
Preparation of methyl- (6R, 7S, 13S) -13-benzyl-8-methyl-7- (2-oxo-2-phenylethyl) -5,7,8, 13-tetrahydro-6H-6, 13-cycloiminobenzo [4,5] cyclooctane [1,2-b ] indole-6-carboxylic acid salt (I-54):
the preparation method of this example is similar to example 1, only the raw materials and reaction conditions are changed during the reaction, the organic solvent used in the preparation process is acetonitrile, the base is triethylamine, the catalyst is 4a, the reaction temperature is 20 ℃, and the reaction time is 6 h.
Characterization data: 91% yield, white solid, melting point: 91.4-92.1 ℃;
1H NMR(400MHz,CDCl3)δ7.69(dd,J＝15.3,7.4Hz,1H),7.59–7.50(m,1H),7.45(t,J＝7.4Hz,1H),7.30(t,J＝7.8Hz,1H),7.15(d,J＝7.6Hz,1H),7.13–7.06(m,2H),7.03(td,J＝8.0,2.3Hz,2H),6.97(t,J＝7.4Hz,1H),6.87(d,J＝7.5Hz,1H),4.42(d,J＝13.1Hz,1H),4.03–3.78(m,1H),3.44(s,6H),3.33–3.15(m,2H),2.93(dd,J＝18.2,6.1Hz,1H),2.52(d,J＝17.8Hz,1H),2.23(dt,J＝20.5,10.2Hz,2H).13C NMR(101MHz,CDCl3)δ196.96,173.67,144.76,136.92,136.88,136.52,135.31,133.37,132.22,130.07,128.08,127.45,127.21,126.39,125.01,124.99,124.85,124.71,123.59,119.96,119.90,118.42,118.37,108.44,108.22,59.93,55.93,51.30,40.53,39.72,37.52,36.09,28.21.
HRMS(ESI)m/z calcd for:C36H32N2O3[M+H]+＝541.2486,found＝541.2488；
The ee value was 92％,tR(major)＝16.0min,tR(minor)＝34.0min(Chiralcel IA,λ＝254nm,5％i-PrOH/hexane,flow rate＝1.0mL/min).dr>20:1.
the nuclear magnetic and mass spectral data show that the product has correct structure.
The above compounds and the preparation method thereof are only some examples listed in the invention, and the rest of the compounds protected by the invention and the preparation method thereof can be used for completing the preparation of different compounds according to alternative raw materials, thereby obtaining different compounds.
Test examples inhibition of tumor cells by the Compounds of the present invention
1. Experimental methods
Experimental cells: HCT116 (human colon cancer cells), BB4 (human lung cancer cells).
Cells in logarithmic growth phase were seeded into 96-well culture plates at 100. mu.L per well. After overnight culture, cells adhere to the wall, and 100. mu.L of a culture medium containing the compound (final concentration: 20. mu. mmol/L) is added to each well of the administration group; only 100. mu.L of the corresponding medium was added to each well of the control group. The incubation was continued for 72h, the old medium was removed, 100. mu.L of fresh medium containing 10% by volume of CCK-8 reagent was added to each well, and medium containing 10% CCK-8 was added to wells of uncultured cells as a blank. Incubating for 2h at 37 ℃, detecting OD values at 450nm and 600nm of each hole by using an enzyme-labeling instrument, and deducting the OD values when calculating by taking 600nm as a reference wavelength.
The calculation method comprises the following steps: the cell inhibition rate at a concentration of 20 μmmol/L was calculated, which was [ (control OD value-administration OD value)/(control OD value-blank OD value) ] × 100%.
2. Results of the experiment
The inhibitory effect of the compounds of the present invention on HCT116 cells at a concentration of 20. mu.M is shown in Table 1. As can be seen from Table 1, the compounds of the present invention have certain inhibition effect on tumor cells, especially the inhibition rate of the compounds I-16, I-20 and I-36 on tumor cells is up to more than 50%, and the IC of the compounds I-16 and I-20 on HCT116 cells50As low as 4.741umol and 3.349umol, respectively, are shown in Table 2). It is worth mentioning that the compound I-20 shows higher inhibition rate than that of the commercially available anti-colon cancer chemotherapeutic drug irinotecan, and the compound has excellent anti-cancer activity and potential.
The inhibitory effect of the compounds of the present invention on BB4 cells at a concentration of 20. mu.M is shown in Table 3. As can be seen from Table 3, the compounds of the present invention have certain inhibition effect on tumor cells, especially the inhibition rate of the compounds I-8, I-11, I-16, I-20 and I-37 on tumor cells is as high as more than 50%.
TABLE 1 inhibitory Effect of the Compounds of the present invention on HCT116 cells at a concentration of 20. mu.M
| Compound numbering | Cell inhibition rate% | Compound numbering | Cell inhibition rate% |
| I-1 | 37.9％ | I-3 | 21.5％ |
| I-2 | 19.3％ | I-37 | 32.8％ |
| I-5 | 29.3％ | I-21 | 29.5％ |
| I-8 | 26.9％ | I-22 | 43.9％ |
| I-7 | 26.8％ | I-23 | 43.8％ |
| I-9 | 23.3％ | I-36 | 50.5％ |
| I-10 | 34.7％ | I-4 | 16.9％ |
| I-12 | 13.0％ | I-24 | 26.7％ |
| I-11 | 23.2％ | I-6 | 29.8％ |
| I-13 | 6.5％ | I-25 | 11.0％ |
| I-14 | 13.6％ | I-26 | 43.8％ |
| I-15 | 8.5％ | I-27 | 41.5％ |
| I-16 | 53.7％ | I-31 | 36.4％ |
| I-17 | 0.9％ | I-32 | 35.3％ |
| I-18 | 21.8％ | I-33 | 28.1％ |
| I-20 | 96.1％ | I-34 | 24.4％ |
| I-19 | 14.3％ | I-35 | 35.2％ |
| Irinotecan | 95.5％ |
Note: irinotecan as a chemotherapeutic drug for colon cancer
TABLE 2 IC of partial compounds of the invention on HCT116 cells50.
TABLE 3 inhibitory Effect of the Compounds of the present invention on BB4 cells at a concentration of 20. mu.M
| Compound numbering | Cell inhibition rate% | Compound numbering | Cell inhibition rate% |
| I-1 | 41.6％ | I-3 | 17.1％ |
| I-2 | 7.5％ | I-37 | 58.2％ |
| I-5 | 46.8％ | I-21 | 39.4％ |
| I-8 | 57.3％ | I-22 | 48.2％ |
| I-7 | 24.2％ | I-23 | 19.6％ |
| I-9 | 13.1％ | I-36 | 42.2％ |
| I-10 | 23.6％ | I-4 | -3.6％ |
| I-12 | 18.5％ | I-24 | 16.6％ |
| I-11 | 50.2％ | I-6 | 20.0％ |
| I-13 | 5.6％ | I-25 | 5.7％ |
| I-14 | 3.7％ | I-26 | 39.0％ |
| I-15 | 18.8％ | I-27 | 32.2％ |
| I-16 | 68.2％ | I-31 | 20.2％ |
| I-17 | 32.0％ | I-32 | 2.6％ |
| I-18 | 34.0％ | I-33 | 12.7％ |
| I-20 | 57.9％ | I-34 | -2.7％ |
| I-19 | 26.9％ | I-35 | 15.9％ |
Claims (9)
1. A chiral [3.3.1] azacycloindole alkaloid derivative comprising the structural formula I and its corresponding enantiomers and diastereomers, or a salt thereof:
wherein,
R1is C1-20Alkyl, phenyl or substituted phenyl, naphthyl, aromatic heterocycles;
R2is hydrogen, C1-20Alkyl, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, chloroformate;
R3is hydrogen, C1-20An alkyl group;
R4is an ester group;
R5is hydrogen, C1-20Alkyl, alkoxy, halogen;
R6is hydrogen, acyl;
ar is aryl or substituted aryl, indole ring or substituted indole ring group, furan, pyrrole, pyridine, thiophene, quinoline, isoquinoline, benzofuran, benzothiophene, benzopyridine.
2. The chiral [3.3.1] azacycloindole alkaloid derivative according to claim 1, having the specific structural formula:
3. a process for the preparation of a chiral [3.3.1] azabridged indole alkaloid derivative according to any of claims 1-2, comprising the steps of:
under the action of chiral quaternary phosphonium salt catalyst, dissolving compound A and compound B in organic solvent, adding alkali,
reacting to obtain chiral [3.3.1] aza-bridged indole alkaloid derivative, namely the compound of formula I; the synthetic route is as follows:
4. the process for the preparation of chiral [3.3.1] azacycloindole alkaloid derivatives according to claim 3, characterized in that the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, ethanol, acetonitrile, toluene or xylene.
5. The process for the preparation of a chiral [3.3.1] azacycloindole alkaloid derivative according to claim 3, characterized in that the base is triethylamine, diisopropylethylamine, DABCO, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate heptahydrate, sodium phosphate decahydrate, sodium hydroxide, potassium hydroxide or lithium hydroxide.
6. The preparation method of the chiral [3.3.1] azacycloindole alkaloid derivative according to claim 3, characterized in that the reaction temperature is-78-40 ℃ and the reaction time is 6-72 h.
7. The method for preparing chiral [3.3.1] azacycloindole alkaloid derivatives according to claim 3, wherein the chiral quaternary phosphonium salt catalyst is:
wherein in the compound IV, R1Is hydrogen, C1-20Alkyl, phenyl or substituted benzenesA group, benzyl or substituted benzyl, heterocycle or substituted heterocycle; r5Is Boc, Ts, acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r6Is C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF4OTf, OAc or OBoc;
in the compound V, R4Is hydrogen, C1-20Alkyl, Boc, Ts, benzyl or substituted benzyl, silyl; r5Is Boc, Ts, acyl or substituted acyl, ureido, thioureido or substituted thioureido, carbonyl or substituted carbonyl; r6Is C1-20Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl; x is halogen, BF4OTf, OAc or OBoc.
8. The method for preparing chiral [3.3.1] azacycloindole alkaloid derivatives according to claim 7, wherein the chiral quaternary phosphonium salt catalyst is:
9. use of a chiral [3.3.1] azacycloindole alkaloid derivative according to any of claims 1-2 for the preparation of a medicament for the prevention and/or treatment of tumors.
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